Table 1.

History of gene therapy vs. vaccine regulation.

Year	Regulatory Agency	Rule	Comment
1996	FDA [13] Points to Consider on Plasmid DNA Vaccines for Preventive Infectious Disease Indications	Plasmid DNA vaccines are defined as purified preparations of plasmid DNA, designed to contain a gene or genes for the intended vaccine antigen, as well as genes incorporated into the construct that allow for production in a suitable host system	No mention of RNA because RNA-based gene therapy was not yet envisaged
1998	FDA [12] content current as of 2021 Guidance for human cell therapy and gene therapy	Virus or DNA preparations used as preventive vaccines are not covered by this document, though there is some overlap in the issues	No mention of RNA because RNA-based gene therapy was not yet envisaged
2003	European Union Directive 2001/83/EC which regulates medicinal products for human use, amended in June 2003 Part IV relating to Advanced Medicinal Products (ATMPs) https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32003L0063&qid=1686154511801, accessed on 8 June 2023	Gene Therapy Medicinal Products (GTMPs) are defined as: “a product obtained through a set of manufacturing processes aimed at the transfer, to be performed either in vivo or ex vivo, of a prophylactic, diagnostic or therapeutic gene (i.e., a piece of nucleic acid), to human/animal cells and its subsequent expression in vivo”	Specific GTMPs included “naked nucleic acid” This definition would include mRNA vaccines
2005	WHO [23]	WHO grant nucleic-acid-based vaccines the status of vaccines	Vaccines must comply with GMP In case of new formulations: distribution studies and toxicology studies for new additives are required
2007	FDA [20]	Manufacturing issues and preclinical required studies for DNA plasmids as vaccine to prevent infectious diseases	DNA plasmids are subject to controls inspired by those for GTP
2009	European Union Directive 2001/83/EC Part IV on ATMPs amended 14 September 2009 [13]	A GTP (a) contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence; and (b) its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence. Gene therapy medicinal products shall not include vaccines against infectious diseases.	Vaccines against infectious diseases are excluded from the GTP regulations No ethical or scientific justification is provided
2013	FDA [21]	Regulation of gene therapy products did not apply to vaccines against infectious diseases	Apply to DNA plasmids
2015	EMA [24] Reflection Paper on Classification of Advanced Therapy Medicinal Products	EMA confirms that vaccines against infectious diseases are not classified as gene therapy products	No ethical or scientific justification is provided
2016	EMA [25]	EMA specifies, in this document, that the non-clinical specific aspects of nucleic acid vaccines must be studied in light of GTP regulations	Does not include mRNAs but the definition provided is not exhaustive